Dopamine D1 receptor (D1R) is an important drug target implicated in many psychiatric and neurological disorders. Selective agonism of D1R are sought to be the therapeutic strategy for these disorders. Most selective D1R agonists share a dopamine-like catechol moiety in their molecular structure, and their therapeutic potential is therefore limited by poor pharmacological properties in vivo. Recently, a class of non-catechol D1R selective agonists with a distinct scaffold and pharmacological properties were reported. Here, we report the crystal structure of D1R in complex with stimulatory G protein (Gs) and a non-catechol agonist Compound 1 at 3.8 Å resolution. The structure reveals the ligand bound to D1R in an extended conformation, spanning from the orthosteric site to extracellular loop 2 (ECL2). Structural analysis reveals that the unique features of D1R ligand binding pocket explains the remarkable selectivity of this scaffold for D1R over other aminergic receptors, and sheds light on the mechanism for D1R activation by the non-catechol agonist.

Significance The A 2A R is a G protein-coupled receptor (GPCR) that plays important roles in cardiovascular physiology and immune function. The A 2A R is also a target for the treatment of Parkinson’s disease, where A 2A R antagonists have been shown to enhance signaling through the D2 dopamine receptor. Here we present the crystal structure of the A 2A R bound to a novel bitopic antagonist. As a result of structural changes needed to accommodate the bound antagonist, crystals could not be grown in lipidic cubic phase. Instead, crystals were grown in detergent with a type II packing rarely observed in GPCR crystals. The structure revealed a potential allosteric pocket that that can be exploited to develop subtype-selective allosteric modulators.

The putative Major Facilitator Superfamily (MFS) transporter, SV2A, is the target for levetiracetam (LEV), which is a successful anti-epileptic drug. Furthermore, SV2A knock out mice display a severe seizure phenotype and die after a few weeks. Despite this, the mode of action of LEV is not known at the molecular level. It would be extremely desirable to understand this more fully in order to aid the design of improved anti-epileptic compounds. Since there is no structure for SV2A, homology modelling can provide insight into the ligand-binding site. However, it is not a trivial process to build such models, since SV2A has low sequence identity to those MFS transporters whose structures are known. A further level of complexity is added by the fact that it is not known which conformational state of the receptor LEV binds to, as multiple conformational states have been inferred by tomography and ligand binding assays or indeed, if binding is exclusive to a single state. Here, we explore models of both the inward and outward facing conformational states of SV2A (according to the alternating access mechanism for MFS transporters). We use a sequence conservation analysis to help guide the homology modelling process and generate the models, which we assess further with Molecular Dynamics (MD). By comparing the MD results in conjunction with docking and simulation of a LEV-analogue used in radioligand binding assays, we were able to suggest further residues that line the binding pocket. These were confirmed experimentally. In particular, mutation of D670 leads to a complete loss of binding. The results shed light on the way LEV analogues may interact with SV2A and may help with the on-going design of improved anti-epileptic compounds.

The dimethyl sulfoxide (DMSO) solubility data from Enamine and two UCB pharma compound collections were analyzed using 8 different machine learning methods and 12 descriptor sets. The analyzed data sets were highly imbalanced with 1.7–5.8% nonsoluble compounds. The libraries’ enrichment by soluble molecules from the set of 10% of the most reliable predictions was used to compare prediction performances of the methods. The highest accuracies were calculated using a C4.5 decision classification tree, random forest, and associative neural networks. The performances of the methods developed were estimated on individual data sets and their combinations. The developed models provided on average a 2-fold decrease of the number of nonsoluble compounds amid all compounds predicted as soluble in DMSO. However, a 4–9-fold enrichment was observed if only 10% of the most reliable predictions were considered. The structural features influencing compounds to be soluble or nonsoluble in DMSO were also determined. The best models developed with the publicly available Enamine data set are freely available online at http://ochem.eu/article/33409.

Botulinum neurotoxin A (BoNT/A) is considered the most toxic substance known but is also used as a therapeutic drug for a growing number of diseases and conditions; researchers have now obtained a high-resolution crystal structure of the receptor-binding domain of the BoNT/A in complex with the luminal domain of synaptic vesicle protein 2C (SV2C), one of its receptors, allowing the identification of a peptide that can inhibit complex formation.

A multi-disciplinary approach was used to identify the first pharmacophore model for KCC2 blockers: several physico-chemical studies such as XRD and NMR were combined to molecular modelling techniques, SAR analysis and synthesis of constrained analogues in order to determine a minimal conformational space regrouping few potential bioactive conformations. These conformations were further compared to the conformational space of a different series of KCC2 blockers in order to identify the common pharmacophoric features. The synthesis of more potent analogues in this second series confirmed the usefulness of this KCC2 blocker pharmacophore model.

LEV (levetiracetam), an antiepileptic drug which possesses a unique profile in animal models of seizure and epilepsy, has as its unique binding site in brain, SV2A (synaptic vesicle protein 2A). Previous studies have used a chimaeric and site-specific mutagenesis approach to identify three residues in the putative tenth transmembrane helix of SV2A that, when mutated, alter binding of LEV and related racetam derivatives to SV2A. In the present paper, we report a combined modelling and mutagenesis study that successfully identifies another 11 residues in SV2A that appear to be involved in ligand binding. Sequence analysis and modelling of SV2A suggested residues equivalent to critical functional residues of other MFS (major facilitator superfamily) transporters. Alanine scanning of these and other SV2A residues resulted in the identification of residues affecting racetam binding, including Ile273 which differentiated between racetam analogues, when mutated to alanine. Integrating mutagenesis results with docking analysis led to the construction of a mutant in which six SV2A residues were replaced with corresponding SV2B residues. This mutant showed racetam ligand-binding affinity intermediate to the affinities observed for SV2A and SV2B.

H(3)R inverse agonists based on an aminopropoxy-phenyloxazoline framework constitute highly valuable druglike lead compounds that display efficacy in a mouse model of recognition memory.

The H3 drug discovery process has been constantly refined from the original idea to the proof-of-concept in human. Along with the preclinical development of potent drug candidates, the need for radiolabeled H3 ligands has been crucial to study the histamine H3-ligand interactions and therefore to run appropriate in vitro binding and functional screening assays. The exponential patent application filings and public disclosures of widely diverse chemical series demonstrated the ability of medicinal chemists to identify key features for high-affinity ligands and transformed their creativity into innovative compounds. Such work has been gratefully supported by computer-aided drug design activities. Chemically diverse hits were found, as exemplified by compound 147, 148, and 149, displaying weak to moderate antagonism properties. In contrast to the classical concept "one disease—one target—one drug," the multiple targeting approaches by a single chemical entity or a combination of compounds are often realized with marketed drugs for complex diseases.

Research on the therapeutic applications of the histamine H-3 receptor (H3R) has traditionally focused on antagonists/inverse agonists. In contrast, H3R acyonists have received less attention despite their potential use in several disease areas. The lower availability of H3R agonists not only hampers their full therapeutic exploration, it also prevents an unequivocal understanding of the structural requirements for H3R activation. In the light of these important issues, we present our findings on 4-benzyl-1H-imidazole-based H3R agonists. Starting from two high throughput screen hits (10 and 11), the benzyl side chain was altered with lipophilic groups using combinatorial and classical chemical approaches (compounds 12-31). Alkyne- or oxazolino-substituents gave excellent affinities and agonist activities up to the single digit nM range. Our findings further substantiate the growing notion that basic ligand sidechains are not necessary for H3R activation and reveal the oxazolino group as a hitherto unexplored functional group in H3R research.

High-throughput screening of the UCB sample collection identified the piperidinyl-sulfonyl benzoic ester 1 as a novel agonist for CB, receptor with nanomolar affinity. We report here the pharmacological profile of compound 1 as well as preliminary biological activities in pain model. Diverse close analogs of 1 were purchased and the structure-affinity relationships among this novel class are discussed. (c) 2006 Elsevier Ltd. All rights reserved.

We have previously developed a new family of organometallic complexes targeting the HIV-1 protease, an enzyme that is essential for viral maturation. Among these, two Cu2+ complexes C1 and C2 were synthesized from flexible ligands L1, N1-(4-methyl-2-pyridyl)-2,3,6-trimethoxybenzamide and L2, N2-(2-methoxybenzyl)-2-quinolinecarboxamide, respectively. These ligands, designed to fit the protease active site, were shown to form 2:1 complexes with Cu2+. To compare the relative stability of C1 and C2 and to study the energetic and structural aspects of such large Cu2+ complexes, we have extended the polarizable molecular mechanics procedure SIBFA to treat this cation. This was done by carrying out parallel ab initio (HF, MP2) as well as DFT computations. A first validation step was done on monoligated complexes, in which the SIBFA energy components were shown to correctly match their ab initio counterparts from an energy-decomposition procedure. Subsequent tests on polyligated Cu2+ complexes with neutral and anionic ligands showed the procedure to reproduce the results from MP2 and DFT computations with good accuracy (relative error <3%). We have next extended the calculations to compare the C1 and C2 complexes. Energy balances including continuum solvation effects indicate a greater stability of the C1 complex, in agreement with experimental results. The effects of the methoxyphenyl substituents on the C1 complex stability were further investigated and compared to their concomitant influences on the ab initio-computed molecular electrostatic potential.

The use of metal-organic complexes is a potentially fruitful approach for the development of novel enzyme inhibitors. They hold the attractive promise of forming stronger attachments with the target by combining the co-ordination ability of metals with the unique stereoelectronic properties of the ligand. We demonstrated that this approach can be successfully used to inhibit the protease of the human immunodeficiency virus (type 1). Several ligands bearing substituents designed to interact with the catalytic site of the enzyme when complexed to Cu2+ were synthesised. The inhibition pattern of the resulting copper(II) complexes was analysed. We showed that the copper(II) complex of N1-(4-methyl-2-pyridyl)-2,3,6-trimethoxybenzamide (C1) interacts with the active site of the enzyme leading to competitive inhibition. On the other hand, N2-pyridine-amide ligands and oxazinane carboxamide ligand were found to be poor chelators of the cupric ion under the enzymatic assay conditions. In these cases, the observed inhibition was attributed to released cupric ions which react with cysteine residues on the surface of the protease. While unchelated metal cations are not likely to be useful agents, metal chelates such as C1 should be considered as promising lead compounds for the development of targeted drugs.